In U.S. controlled studies, nonfasting cholesterol increases to greater than or equal to 20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to greater than or equal to 500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.
Clinically significant ALT (SGPT) elevations (greater than or equal to 3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to mirtazapine in a pool of short-term U.S. controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine should be used with caution in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of mirtazapine-treated patients in U.S. studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.
In premarketing clinical trials, only 1 seizure was reported among the 2,796 U.S. and non-U.S. patients treated with mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.
Clinical experience with mirtazapine in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses.
Mirtazapine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. Mirtazapine should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).
Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11 mL/min/1.73 m2 to 39 mL/min/1.73 m2 ] and severe [GFR less than 10 mL/min/1.73 m2 ] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering mirtazapine to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine.
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Patients who are to receive mirtazapine should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
Mirtazapine may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines, or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine therapy does not adversely affect their ability to engage in such activities.
While patients may notice improvement with mirtazapine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for mirtazapine to interact with other drugs.
Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s wort, is clinically warranted, particularly during treatment initiation and dose increases.
The impairment of cognitive and motor skills produced by mirtazapine has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine therapy.
Patients should be advised to notify their physician if they are breast-feeding an infant.
There are no routine laboratory tests recommended.
As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY).
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